tbuckley/cabot-search huggingface dataset:
Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) for patients with pleural metastases from thymic malignancies.
Authors: Andreas Rimner, James Huang, Andrew Pagano, Michelle S. Ginsberg, Jason C. Chang, Gregory J. Riely, Charles B. Simone, Daniel Richard Gomez, Annemarie Shepherd
Journal: Journal of Clinical Oncology (2023)

TPS8616 Background: Pleural metastases are common sites for recurrence and progression in patients with thymic malignancies. The management of pleural metastases typically involves surgical resection with or without neoadjuvant or adjuvant systemic therapy. After surgical resection of pleural metastases, the 5-year progression-free survival (PFS) rate is about 29-45%. While radiation therapy (RT) is standardly used in the management of locally-advanced thymic malignancies, the role of RT in patients with pleural metastases in unclear. Intensity-modulated pleural radiation therapy (IMPRINT) is a RT technique currently being used to treat malignant pleural mesothelioma (MPM) patients with 2 intact lungs at centers that specialize in MPM treatment. This IMPRINT technique can potentially be extrapolated to thymic patients with pleural metastases. Because the risk of toxicity is of greater concern for thymic patients given their overall relatively favorable prognosis, the rate of toxicity, particularly radiation pneumonitis, needs to be established in the thymic patient population. Methods: This is a single-arm, single institution Phase II study of hemithoracic IMPRINT for patients with pleural metastases from thymic malignancies. The primary endpoint of this study is grade 3 or higher radiation pneumonitis within 4 months of completing RT. Secondary endpoints include any toxicity, progression-free survival, patterns of failure and overall survival. Patients must have a pathologically confirmed diagnosis of a thymic malignancy with radiologic or pathologic evidence of pleural metastases. Thymoma or thymic carcinoma are allowed. Patients may have de novo stage IVA disease or recurrent disease in the pleura. There must be no evidence of extrathoracic metastatic disease or contralateral pleural/pericardial disease. Surgical resection of the pleural nodules (ex: pleurectomy/decortication, debulking/metastasectomy) are allowed. Extrapleural pneumonectomy is not allowed. Patients are excluded if they have undergone prior thoracic radiation therapy preventing hemithoracic pleural IMRT, whereas prior thymic bed radiation and/or prior pleural SBRT are allowed. RT will be administered to the ipsilateral pleura to 50.4 Gy in 28 fractions. An optional dose-painting boost to gross disease up to 60 Gy while respecting normal tissue constraints is allowed. Patients can be treated with photon or proton therapy. Simulation, contouring and RT planning guidelines have been developed. Patients will be followed per protocol at regular intervals for at least 12 months following RT. The expected accrual is 36 patients over 4 years. Further information can be found on clinicaltrials.gov (NCT05354570). Clinical trial information: NCT05354570 .
Colorectal cancer screening with blood-based tests: Estimated impact of a 1-, 2-, or 3-year screening interval compared with annual FIT and triennial mt-sDNA strategies.
Authors: A. Mark Fendrick, John B. Kisiel, Derek W. Ebner, A. Burak Ozbay, Vahab Vahdat, Chris Estes, Paul J. Limburg
Journal: Journal of Clinical Oncology (2023)

10580 Background: Blood-based tests are an emerging option for non-invasive colorectal cancer (CRC) screening for which the Centers for Medicare &amp; Medicaid Services (CMS) has proposed coverage every 3 years for average-risk individuals. Analyses with the CRC-AIM microsimulation model demonstrated that triennial screening with blood-based tests with CMS minimum performance often yields inferior outcomes to stool-based CRC screening (fecal immunochemical test [FIT] and multi-target stool DNA [mt-sDNA]). CRC-AIM was used to explore the impact of blood-based screening intervals, using reported performance characteristics from the ECLIPSE study (Guardant Health, Inc.) 1 , on estimated clinical outcomes vs FIT and mt-sDNA screening. Methods: Outcomes were simulated for average-risk individuals screened between ages 45-75 years. Intervals were set at 1, 2, or 3 years for blood-based, 3 years for mt-sDNA and annually for FIT screening. The blood-based test was modeled at 83% CRC sensitivity, 13% advanced adenoma sensitivity, and 90% specificity. Perfect adherence (100%) was modeled for blood-based tests and real-world adherence rates used for CRC initial screening tests (mt-sDNA=65.6%; FIT=42.6%) and follow-up colonoscopy (mt-sDNA=72.1%; FIT=46.0%). Primary outcomes were life-years gained (LYG) and colonoscopies (COL) per 1000 individuals for blood-based screening compared to mt-sDNA and FIT. As a secondary analysis, estimates were generated with perfect (100%) adherence assumed for initial screening and follow-up colonoscopy for mt-sDNA and FIT as well. Results: Blood-based testing at a 3-year interval with 100% adherence led to 11% fewer LYG than mt-sDNA at RWE adherence (240 vs 270, respectively), and 9% more COL (1402/1000 vs 1288/1000). Meanwhile, blood-based testing at a 1-year interval and perfect adherence (best case scenario) resulted in the lowest LYG per COL ratio across all scenarios (16% more LYG and 87% more COL compared to mt-sDNA at RWE adherence). Blood-based test results showed similar trends when compared to FIT. Conclusions: Outcomes for blood-based screening every 3 years based on reported test performance characteristics and unrealistic perfect adherence demonstrate fewer LYG as compared to either mt-sDNA or FIT. When compared to real-world adherence for mt-sDNA and FIT, blood-based tests with 1- and 2-year intervals and perfect adherence had higher LYG with the tradeoff of a greater number of diagnostic colonoscopies. [Table: see text]
Clinical application of ctDNA detection in Chinese pediatric patients with soft tissue sarcoma (STS).
Authors: Jia Zhu, Suying Lu, Juan Wang, Feifei Sun, Junting Huang, Yi Que, Zijun Zhen, Xiaofei Sun, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2023)

10041 Background: Circulating tumor DNA (ctDNA) is an effective and noninvasive supplementary approach for assessing minimum tumor burden in a range of solid tumors; however, studies on pediatric soft tissue sarcoma (STS) are limited. The purpose of the study was to assess the utility of ctDNA detection in predicting patient response and recurrence, and to inform treatment strategies through dynamic monitoring of ctDNA during the treatment of various types of pediatric STS. Methods: From January 2022 to January 2023, a total of 27 tissues and 112 plasma samples were obtained at baseline and during treatment. Utilizing the next-generation sequencing approach, ctDNA profiling was performed on tissue and plasma samples from 48 pediatric STS ( &lt; 18 years old) with a panel of 481 sarcoma-specific genes (Nanjing Geneseeq Technology Inc.). Results: The study included thirty patients with rhabdomyosarcoma, nine Ewing sarcoma, and nine other subtypes of sarcoma, with 52.1% (n = 25) female. Seven patients were stages I-II, and 24 were stages III-IV. At baseline, ctDNA was identified in 56.25 % (18/32) of plasma before chemotherapy and 87.50 % (14/16) of plasma before surgery. Comparable mutational burdens were seen in baseline tissue and plasma samples, with an average of 3.8 and 3 mutations per sample, respectively. The concordance of detected mutations between tissue and plasma was 64.3%. The average plasma abundance (p = 0.007), maximum abundance (p = 0.0045), ctDNA concentration (hGE/ml) (p = 0.0005), and relative ctDNA abundance (p = 0.0083) of stage IV patients (n = 5) were higher than those of stage I-III patients (n = 6). Following surgical resection, four patients (25 %, 4/16) had detectable ctDNA. In the longitudinal monitoring, we found a high correlation (75.86 %, 22/29) between ctDNA trend and clinical response. Notably, ctDNA positive in Ewing sarcoma had the strongest correlation with clinical response. The inconsistency between ctDNA detection and clinical response could be attributed to the presence of bone lesions (57.1%, 4/7). One patient was observed to have positive ctDNA before any radiological findings. Conclusions: Our findings showed that it is feasible to use ctDNA to dynamically monitor tumor burden in pediatric soft tissue sarcoma, especially Ewing sarcoma. ctDNA may serve as a safe, non-invasive option complementary to imaging assessment of sarcoma, and further clinical benefits are being investigated.
Updated safety and efficacy results of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.
Authors: Dawei Chen, Aiqin Gao, Wei Huang, Qian Shao, Xiangjiao Meng, Xiaoyong Tang, Pinliang Zhang, Xudong Hu, Yan Zhang, Jun Guo, Lei Fu, Wei Zhao, Changhong Zhao, Jiajia Yuan, Jinming Yu, Linlin Wang
Journal: Journal of Clinical Oncology (2023)

8580 Background: CAPSTONE-1 study showed that SHR-1316 (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival in patients (pts) with ES-SCLC. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts included in this study received 4~6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin, 75mg/m², D1-3, q3w or carboplatin, AUC = 5, D1, q3w and etoposide, 100mg/m 2 , D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved-field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to January 2023, 63 pts with ES-SCLC were enrolled and received at least one dose of SHR-1316, 33 of them have received chest radiotherapy. The median age was 63 (range: 38-75), and most pts were male (53, 84.1%), former smokers (42, 66.7%) with an ECOG performance status 1 (60, 95.2%). At baseline, 24 (38.1%) pts were diagnosed with brain metastasis and 19 (30.2%) pts had liver metastasis. At the data cutoff date, the average number of treatment cycles was 6.9, 17 pts remained on treatment. 55 pts had at least one post-treatment tumor assessment. 41 pts achieved a confirmed partial response, and 12 pts had stable disease. The confirmed ORR and DCR were 74.5% and 96.4%, respectively. The median PFS was 7(CI: 4.3~9.7) months. Adverse events (AEs) occurred in 47 (74.6%) pts. Grade 3 or 4 AEs occurred in 35 (55.6%) pts. The most common grade 3 or 4 AEs included neutropenia (27, 42.9%), leukopenia (13, 20.6%), lymphocytopenia (5, 7.9%), pneumonia (4, 6.3%), anemia (3, 4.8%), and thrombocytopenia (2, 3.2%). Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337 .
Association of circulating tumor DNA kinetics with disease recurrence in patients with stage IIIB/C/IV melanoma treated with adjuvant immunotherapy in Checkmate 238.
Authors: Mahrukh M. Syeda, Jennifer M Wiggins, Josephine Alegun, Saim Ali, Hao Tang, Sheen Wang, Kao-Tai Tsai, Keyur Desai, Sonia Dolfi, Daniel J. Tenney, Paolo Antonio Ascierto, James Larkin, Michele Del Vecchio, Jeffrey S. Weber, David Polsky
Journal: Journal of Clinical Oncology (2023)

9577 Background: In patients (pts) with resected, stage III/IV melanoma receiving adjuvant immunotherapy, pre-treatment (pre-Tx) and on-treatment (on-Tx) circulating tumor DNA (ctDNA) combined with tumor features were evaluated to predict recurrence risk. Methods: We used analytically validated, mutation-specific droplet digital PCR (ddPCR) assays to measure ctDNA in pre- and on-Tx plasma samples from pts with resected stage IIIB/C/IV melanoma enrolled in CheckMate 238 (NCT02388906) receiving either adjuvant Nivolumab (NIVO) or Ipilimumab (IPI). Assay choice was based on detection of one of the 7 melanoma hot-spot mutations in pt tumors: BRAF V600E/K, NRAS Q61R/L/K, or TERT C228T/C250T. We evaluated associations between ctDNA detection, recurrence free survival (RFS), distant metastasis free survival (DMFS), and known immunotherapy tumor biomarkers including PD-L1, IFNg gene signature, CD8, and tumor mutational burden. Associations between ctDNA kinetics and RFS/DMFS were analyzed using Kaplan-Meier and Cox regression models. Results: Mutations were identified in 87% of tumors. ctDNA was detected in pre-Tx samples from 94/753 (12.5%) pts. Pre-Tx ctDNA was significantly associated with higher stage of disease, LDH ≥ ULN, PD-L1 &lt; 5%, and tumor IFNg-RNA signature expression below the median. Detection of pre-Tx ctDNA was associated with shorter RFS and DMFS in both NIVO and IPI arms compared to undetectable ctDNA (Table). ctDNA detection on-Tx (week (w) 3, 7, 13, 25, 37, 49) was also associated with shorter RFS. Refined subgroup predictions that potentially impact therapy were achieved by incorporating pre- and on-Tx time points. Of those with baseline and w7 ctDNA results, pts in the NIVO arm with undetectable pre-Tx ctDNA (n=308) that became positive at w7 (n=22) had shorter RFS (median RFS 20.68 mos [95% CI, 2.79, NR]) than pts in whom on-Tx ctDNA remained undetectable (n=286) (median RFS, NR [95% CI, 61.1, NR]). Pts with positive pre-Tx ctDNA (n=42) that remained positive at w7 (n=23) had markedly shorter RFS (median RFS, 3.35 mos [95% CI, 2.73, 20.44]) vs pts in whom on-Tx ctDNA became undetectable (n=19) (median RFS, NR [95% CI, 14, NR]). Similar results were observed in the IPI arm. Conclusions: Pre- and on-Tx ctDNA measurements are associated with melanoma recurrence risk during adjuvant checkpoint inhibitor therapy. Incorporation of ctDNA with other tumor molecular features may improve prediction of RFS and DMFS in this setting. Clinical trial information: NCT02388906 . [Table: see text]
CAROLINE study: Incidence and characterization of melanoma in French Polynesia.
Authors: Nicolas Epaillard, Edouard Auclin, Elodie Hirigoyen, Luc Bermond, Anouck Bonnet, Pierre Loiselet, Mathilde Chastenet, Robert Herve, Sylvie Mengue, Jean Philippe Dutin, Charles Honoré, Pierre Gustin, Linda Mahjoubi
Journal: Journal of Clinical Oncology (2023)

e21505 Background: Epidemiology of metastatic melanoma in French Polynesia has never been described. Yet melanoma is known to be associated with sun exposure. The aim of this monocentric study was to assess the epidemiology of metastatic melanoma in French Polynesia. Methods: Here we analyzed data of all patients diagnosed with metastatic melanoma from January 2015 to December 2020 in the only public hospital in French Polynesia and described epidemiological, survival findings and molecular characteristics. Clinical, molecular and radiological data were collected. Results: Out of 69 patients, the majority were male (74%) and median age was 65 years old. Patients were more often native from French Polynesia (59%) and Metropolitan France (32%), 80% of patients were living in Tahiti Island. Most patients had metastatic cutaneous melanoma and only 3 had metastatic uveal melanoma. A total of 37 patients had an available BRAF molecular profile and 35% were BRAF mutated. 28% were metastatic at diagnosis. First line treatments were nivolumab (31%) and pembrolizumab (15%). The ORR was 45.88% (15/33) and 2 patients had CR. Overall, the median OS was 12.2 months [95% CI, 8.64- 43.27]. Conclusions: Most patients with metastatic melanoma were from Tahiti Island and there were no major disparities between the other archipelagos. Yet facilities of access to care may vary from geographical zones. Massive prevention is still crucial.
Phase 1 dose-expansion study of oral TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, in patients with Ewing sarcoma (EWS).
Authors: Gregory Michael Cote, Andrew J. Wagner, John A. Charlson, James S Hu, Mark Andrew Dickson, Gina Z. D'Amato, Sujan Kabir, Bo Xu, Claudia Lebedinsky, Margaret von Mehren
Journal: Journal of Clinical Oncology (2023)

TPS11589 Background: Cyclin-dependent kinase 9 (CDK9) blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as myeloid cell leukemia-1 (MCL-1) and c-MYC. CDK9 overexpression has been observed in sarcoma patients (pts), and CDK9 has emerged as a potential therapeutic target in pts with sarcoma. TP-1287 is an investigational orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. In preclinical studies, TP-1287 has been shown to decrease MCL-1 expression and phosphorylation of RNA polymerase II (RPB1), and inhibit tumor growth in an Ewing sarcoma (EWS) mouse model. Phase 1 dose-escalation in solid tumors has completed and TP-1287 is being investigated in a dose expansion cohort in pts with EWS (NCT03604783). The design of the expansion part of the trial in pts with EWS is herein described. Methods: Up to thirty pts with EWS will be enrolled in this dose expansion cohort. Key eligibility criteria are age ≥18 years (≥12 years, if weight ≥40 kg); histologically confirmed locally advanced or metastatic unresectable EWS; received 1 to 5 prior lines of treatment including an anthracycline; one or more measurable tumors per the RECIST v1.1; ECOG performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status; no treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives. Eligible pts will be treated with oral TP-1287 monotherapy RP2D established from the dose escalation part (11 mg BID, continuous dosing in a 28-day treatment cycle) and will continue treatment until treatment-related adverse event or disease progression. Assessments will be performed on Day 1 and Day 15 of each cycle. Tumor response assessment will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objectives are objective response rate (ORR) and clinical benefit rate (CBR) ; secondary objectives are median progression-free survival (PFS), PFS rate at 16-weeks and 24-weeks and safety; and exploratory objectives include evaluation of systemic exposure and pharmacodynamics. Safety data will be reviewed on an ongoing basis and a Bayesian approach will be used to assess the efficacy data. Statistical analysis for safety and efficacy parameters will be primarily descriptive in nature. EWS dose expansion cohort is currently recruiting in the United States. Clinical trial information: NCT03604783 .
Phase I study of anlotinib in pediatric patients with high-risk, recurrent, or refractory sarcomas.
Authors: Suying Lu, Juan Wang, Feifei Sun, Junting Huang, Jia Zhu, Ruiqing Cai, Zijun Zhen, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2023)

e23538 Background: Anlotinib is an orally available, highly potent, novel multitargeted tyrosine kinase inhibitor, which blocks VEGF signaling by selectively targeting VEGFR-2, -3 as well as FGFR-1, -2, -3, -4 with high affinity. We evaluated the toxicity, and pharmacokinetic profile of anlotinib in children with high-risk, recurrent, or refractory sarcomas. Methods: This was an open-label, single-center, single-arm phase I study, which enrolled pediatric patients with sarcoma. Pediatric patients aged 5-18 years diagnosed with high-risk, recurrent, or refractory sarcomas were enrolled and further categorized into cohort A (＜35 kg) or cohort B (≥ 35kg). Anlotinib was administered orally, once daily, 2-week on off, until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reasons. A fixed anlotinib level of 8 mg was given to cohort A and three dose levels (8mg, 10mg, 12mg) were evaluated using a “3 + 3” design in cohort B. Results: Between December 29, 2020, and September 7, 2022, 34 patients were enrolled to evaluate the safety and 19 (55.9%) were evaluable for efficacy. The median age was 12 (range 5-18) years old. The main subtype eligible was rhabdomyosarcoma (23.5%). Two of fifteen patients in cohort A at a dose level of 8 mg experienced dose-limiting toxicity, including grade 3 hematuria and grade 3 hand-foot syndrome. The grade 3 treatment-related adverse events (AEs) included neutropenia (3 [8.8%]), hand-foot syndrome (2 [5.9%]), headache (1 [2.9%]), hematuria (1 [2.9%]), hypertension (1 [2.9%]), and hyperbilirubinemia (1 [2.9%]). The most common AEs were grade 1 or 2 hypothyroidism (58.8%) and abdominal pain (55.9%). Twelve of 19 (63.2%) patients had a best response of stable disease with seven patients receiving ≥ 6 cycles. Age has no significant effect on the level of body exposure per unit body surface area dose, and patients younger than 12 years old had a faster elimination. Conclusions: Anlotinib in pediatric patients with sarcoma was well tolerated. The RP2D of anlotinib for future studies is 8 mg for patients＜ 35 kg and 12 mg for patients with ≥ 35kg. Clinical trial information: NCT04659733 . [Table: see text]